CD3、CD73、A2A腺苷受體在卵巢癌的表現及其臨床意義

Abstract

卵巢癌目前是台灣女性癌症死因的第七位，也是婦科癌症中死亡率最高的一種癌症。卵巢癌在初期不易診斷，通常定診斷時，已經到了癌症晚期，造成病人預後不佳。晚期癌症的病人即使經過標準治療，多數還是會面臨復發的問題。 宿主的免疫系統跟對腫瘤的免疫反應是影響卵巢癌預後的重要因子。但腫瘤細胞本身會發展出各種抑制宿主免疫系統的機制，腺苷反應途徑(adenosine pathway)負責了一部分腫瘤免疫抑制的功能。在腫瘤微環境中，腫瘤細胞、免疫細胞及內皮細胞會表現兩種胞外酶：CD39和CD73，在腫瘤微環境中產生及調節腺苷。腺苷受體中以A2A受體與免疫抑制最相關。在卵巢癌中，已有研究顯示在漿液型卵巢癌中發現CD73和預後的相關性，但目前仍缺乏其他組織型別的研究，也較少有合併三種分子同時分析的報告。此研究欲探討在不同組織型別中CD39、CD73、A2A受體在上皮性卵巢癌的基因表現量及與臨床變項之關係以及分析D39、CD73、A2A受體的表現量與卵巢癌預後之相關性。 本研究於病患接受卵巢癌手術時採取癌組織檢體並從中提取RNA，在利用即時定量聚合酶鏈反應定量CD39、CD73、A2A受體基因表現量，在分析基因表現量與臨床變項及預後之關係。 本研究共納入92名上皮性卵巢癌患者，其中包括65名漿液型、9名類內膜樣型、18名亮細胞癌。研究發現三種分子表現量在同一檢體中並不一致，CD39及A2A受體的表現量高度相關（相關係數=0.87），但CD39及CD73的表現相關性不佳（相關係數=0.25）。在不同組織型別中，亮細胞癌中三種分子表現量顯著性較高。在早期卵巢癌中及手術後殘存腫瘤體積小於1公分者中也發現三種分子表現量較高。在與癌症預後的關係發現，在早期卵巢癌中，有癌症復發的病人CD39（p = 0.038）與A2A受體（p = 0.019）表現量顯著較高，但在存活分析及多變項復發或死亡風險迴歸分析中，三種分子表現量的高低皆不是影響預後的獨立因子，影響預後的因子為癌症分期、組織型別及手術殘存腫瘤大小。 總結本研究的發現，三種分子的基因表現量並非完全一致。而亮細胞癌及早期癌症中三種分子的表現量都顯著性高。但除了在早期卵巢癌中復發的病人可見CD39及A2A受體表現量較高外，其他未能發現CD39、CD73、A2A受體在癌組織中的表現量與預後的關係。

Ovarian cancer is a malignancy that is the 7th leading cause of death of female cancer. Most of patient with the presence of the advanced disease will develop recurrence even after primary treatment. The host immune cell and response are related to the prognosis of ovarian cancer, but the tumor could develop different immune-escaping mechanisms. The cancer-derived adenosine pathway, which is mediated by two enzymes, CD39 and CD73 accounted for part of immunosuppression in the tumor microenvironment. Among four types of adenosine receptor, the A2A receptor (A2AR) plays the important roles in immunosuppression in tumor microenvironment. In this study, we aimed to analyze and quantitation the expression of CD39, CD73 and A2AR in the cancerous tissue in different histology types of ovarian cancer patients and to elucidate the correlations of the expression of CD39, CD73 and A2AR between the clinico-pathologic characteristics and prognosis. Women with operated ovarian carcinoma in National Taiwan University hospital and histologic types of serous, endometrioid, and clear cell carcinoma were included. Demographic and clinical data were retrieved from medical records in the hospital’s centralized database. We used Real-time Quantitative Polymerase Chain Reaction (qRT-PCR) to detect the expression of CD39, CD73 and A2A receptor. Total 92 woman were enrolled. 65 patients were diagnosed as serous carcinoma, 9 patients as endometrioid carcinoma and 18 patients as clear cell carcinoma. We found that all three molecules had significantly higher expression in clear cell carcinoma. The woman with early stage and residual tumor less than 1cm were also showed higher expression of all three molecules. In the subgroup analysis of early-staged group, significant higher expression of CD39 and A2AR were found in recurrence cases. For prognosis analysis, stage was the only risk factor of recurrence of ovarian cancer, and stage and residual tumor more than 1cm were risk factor of death. CD39, CD73 and A2AR were not the risk factor of recurrence or death of ovarian cancer in our study. Finally, progression free survival and overall survival showed no significance difference between the high and low expression level of CD39, CD73 and A2AR. In conclusion, this study found CD39, CD73 and A2AR had higher expression in clear cell carcinoma and early-staged cancer. In early-staged patients, higher expression of CD39 and A2AR were found in recurrent patients. The expression of CD39, CD73 and A2AR were not the risk factor of progression free survival and overall survival.